Canonical Question
Antihypertensive
Master answer
Beta receptor antagonists (Beta blockers)
- bind to beta-adrenoceptors and block the binding of noradrenaline and adrenaline
- Inhibits normal sympathetic effects that act through these receptors (Sympatholytic)
- mostly competitive antagonists, there is some evidence of partial agonist activity (Labetalol)
- Some (partial agonists) show intrinsic sympathomimetic activity (ISA): partially activate receptor + prevent noradrenaline from binding to the receptor.
- Some possess membrane stabilizing activity (MSA) similar to sodium-channels blockers
- variable specificity for beta 1 versus beta 2 receptors
- important clinically due to different effects
- often dose related, may be B1 selective at low doses but non-selective at higher
- lipid solubility determines speed of onset
- most resemble isoproterenol
Effects of β-adrenergic blockade
| Type | Main site of action | Effects of β-adrenergic blockade |
|---|---|---|
| β1 | Heart | Anti-ischemic effect: β1 blockade → ↓ heart rate and ↓ cardiac contractility → ↓ BP and ↓ oxygen consumption by the heart → anti-ischemic effect |
| Antiarrhythmic effect: β1 blockade → ↓ AVN conduction, ↑ AVN refractory time, and ↓ heart rate → anti-arrhythmic effect | ||
| Anti-remodeling effect | ||
| Kidneys | β1 blockade of the juxtaglomerular cells → ↓ renin release → ↓ angiotensin II conversion → ↓ H2O resorption → ↓ BP | |
| β2 | Smooth muscle | Vasculature: vasoconstriction Bronchioles: bronchoconstriction |
| Ciliary body of the eye | ↓ Aqueous humor production → ↓ intraocular pressure | |
| Pancreatic beta cells | ↓ Insulin release → hyperglycemia and new-onset diabetes | |
| Skeletal muscle | ↓ Glucose uptake (↓ insulin sensitivity) | |
| Liver | ↓ Hepatic glycogenolysis → hypoglycemia (esp. in diabetics) | |
| Lipoprotein lipase enzyme | Inhibits lipoprotein lipase → ↑ triglycerides and ↓ HDL → hyperlipidemia | |
| β3 | Adipose tissue | ↓ Lipolysis → weight gain |
Classification
- β1-selective (cardioselective):
- e.g. esmolol, nebivolol, bisoprolol, atenolol, metoprolol
- is used for rate control in tachycardia and hypertension management
- side effects: hypotension, heart block, bronchoconstriction at higher doses
- Non-selective β-blockade
- e.g. propranolol
- used for hypertension, to reduce bleeding risk in oesophageal varices, tremor, and as migraine prophylaxis. It is the treatment of choice in thyrotoxicosis as it stops conversion of T4 to T3, reduce ocular pressure in glaucoma
- side effects: rapid withdrawal may precipitate tachycardia, can cause bronchoconstriction and is not recommended in patients with obstructive respiratory disease, issues with hypoglycaemia
- Non-selective α- and β-blockade
- e.g. labetalol, carvedilol
- Potent vasodilators because of their α-blocking action
- Improve endothelial function and vascular re-modelling
- Others
- e.g. sotalol : also acts on K+ channels as class III antiarrhythmic
METOPROLOL | ESMOLOL
PHARMACOKINETICS
| Metoprolol | Esmolol | |
| relatively selective beta blocker with no intrinsic sympathomimetic activity. | Cardio-selective beta blocker with rapid onset and offset. | |
| PK – A | bioavailabilty Absoption is rapid and complete, however there is extensive first pass metabolism. BA 50% routes of admin PO or IV dose Oral in 12.5mg increments, IV in 1-2mg boluses | bioavailabilty Only available as IV therefore 100% routes of admin IV dose In 10mg increments titrate to effect |
| D | volume of distrib 5.5 L/Kg protien binding 10-20% to albumin lipid solubility is high so it crosses the BBB | volume of distrib 3.5 L/Kg protien binding 60% to albumin lipid solubility is high so it crosses the BBB |
| M | hepatic or renal Extensively hepatic via CYP2D6 | neither hepatic or renal! by red blood cell esterases to a mostly inactive metabolite |
| E | half life 3-8hours excretetion In urine 5-10% unchanged | half life 10 minutes excretion In urine |
Sources: CVPharmacology
JC 2019
Exam appearances
| Exam | Exact wording | Relationship | Success |
|---|---|---|---|
| 2019B Q14 | Outline the classification and effects of beta-blocking drugs with examples (50% of marks). Compare and contrast the pharmacokinetics of metoprolol with esmolol (50% of marks). | historical_member | — |
| 2021B Q09 | Outline the classification and effects of beta-blocking drugs, including examples (50% marks). Compare and contrast the pharmacokinetics of metoprolol with esmolol (50% marks). | historical_member | — |